Analysis of a Novel AVPR2 Mutation in a Turkish Family with Nephrogenic Diabetes Insipidus

Congenital nephrogenic diabetes insipidus (NDI) is a rare X-linked recessive disorder associated with germline mutations of the arginine vasopressin (AVP) receptor type 2 (AVPR2) gene. The researchers describe a novel mutation in the AVPR2 gene in a three-generational Turkish family with NDI. In the present report, a 22-year-old man is reported with polyuria and bilateral non-obstructive hydronephrosis. He was diagnosed with partial NDI based on the clinical phenotype, the water deprivation test and the inadequate response to 1-desamino-8-Darginine vasopressin (DDAVP) administration. All family members who were suspected to have diabetes insipidus and/or related symptoms were studied. Sequencing analysis of the AVPR2 gene revealed the novel missense mutation c.392 T>C; p. Leu 131 Pro:L131P (AVPR2 gene (coding seq # NM_000054.4;prot seq # NP_000045.1). In conclusion, the proband carries a novel AVPR2 missense mutation inherited from his carrier mother. Address for correspondence: Dr. C. Nur Semerci Pamukkale University Hospital Department of Medical Genetics Doktorlar Cad. Bayramyeri Denizli, Turkey 20020 Fax: 2136352 E-mail: [email protected] INTRODUCTION The hormone arginine vasopressin (AVP) which is secreted from neurohypophysis is, in part, responsible for maintaining proper water homeostasis in response to rising plasma osmolality by means of binding to arginine vasopressin receptor 2 (AVPR2). AVPR2 is in the basolateral plasma membrane of renal collecting duct principal cells, thereby inducing, after AVP stimulation, apical plasma membrane insertion of aquaporin-2 (AQP2) leading to increased water uptake and urine concentration. Disruption of this mutual hormone-organ relationship causes diabetes insipidus which is characterized by excretion of abnormally large volumes of dilute urine, which results in polyuria and polydipsia. Central diabetes insipidus is a result of absent or diminished antidiuretic hormone due to diseases in hypothalamo-hypophysial region whereas in nephrogenic (NDI) form there is resistance to the action of vasopressin (Fujiwara et al. 2005; Moeller 2013; Robertson et al. 2001). NDI can be either inherited or acquired, almost 90% of congenital NDI is inherited in an X-linked recessive manner due to mutations in the AVPR2 gene residing in the Xq28 region, while 10% is autosomal NDI caused by mutations in the aquaporin 2 gene (AQP2) (Anesi et al; Moeller 2013; Wesche et al 2012). NDI associated mutations in AVPR2 result in a loss of function of V2R signaling, characterized by an inability of this receptor to generate sufficient cAMP in response to AVP. At least 200 different mutations in AVPR2 gene have been reported (Spanakis et al. 2008) AVPR2 mutations disrupt receptor function at various levels, such as impairment of ligand binding, defective intracellular transport and reduced receptor transcription (Fujiwara et al. 2005; Moeller 2013). In this study, the researchers described a novel mutation in the AVPR2 gene in a threegenerational Turkish family with NDI and discussed with other mutations that were reported in the literature. MATERIAL AND METHODS